Obesity is reaching epidemic proportions in western societies and over 65% of the adult U.S. population is either overweight or obese and will likely suffer clinical cardiovascular complications in the years ahead. In order to develop rational therapeutic approaches to treat the cardiovascular conditions attributable to obesity we need to first develop a comprehensive understanding of the molecular mechanisms of obesity-associated cardiovascular risk. Recent studies have documented the importance of the lipid second messenger, ceramide, in a variety of disorders including obesity, diabetes and atherosclerosis. The overall goal of this proposal is to use the pro-thrombotic cardiovascular risk gene, plasminogen activator inhibitor-1 (PAl-l), as a read out, to evaluate the role played by ceramide in the cardiovascular risk associated with obesity.
In Aim 1 we will initially test the hypothesis that the levels of ceramide itself are elevated in adipose tissues in obesity, and that the hyperinsulinemia and elevated TNF-alpha associated with obesity contribute to this increase.
In Aim 2, we will use PAl-1 as a read-out to test the hypothesis that ceramide and/or its bioactive metabolites, sphingosine and sphingosine-l-phosphate, are important regulators of cardiovascular risk in obesity, and that this pathway also contributes to obesity-associated increase in PAl-1 mediated by insulin and TNF-alpha. We also will determine signaling mechanisms that link ceramide to PAl-1 expression in the adipocyte. Finally, in Aim 3, we will test the hypothesis that membrane-bound TNF-alpha in the adipose tissue/adipocytes is an important mediator of increased ceramide and PAl-1 in obesity. These studies will not only advance our understanding of the molecular mechanisms that contribute to the induction of PAl-l, a gene that is consistently up regulated in obesity and positively correlated with cardiovascular risk, but will be clinically significant as they may directly identify novel pathways that link obesity to increased cardiovascular risk.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL071146-01A2
Application #
6821011
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Ershow, Abby
Project Start
2004-07-15
Project End
2009-06-30
Budget Start
2004-07-15
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$491,425
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
941462285
City
San Diego
State
CA
Country
United States
Zip Code
92121
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